4.1. Therapeutic indications

Pluvicto is indicated for the treatment of adult patients with

• prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have progressed on or after treatment with androgen receptor pathway inhibitor (ARPI) therapy and are considered appropriate to delay taxane-based chemotherapy.

• Pluvicto is indicated for the treatment of adult patients with prostate‑specific membrane antigen (PSMA)‑positive metastatic castration‑resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane‑based chemotherapy or who are not medically suitable for taxanes.

4.2. Posology and method of administration

Important safety instructions

Pluvicto should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings (see section 6.6) and after evaluation of the patient by a qualified physician.

Radiopharmaceuticals, including Pluvicto, should be used by or under the control of healthcare professionals who are qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorised to license the use of radiopharmaceuticals.

Pluvicto is a radiopharmaceutical and should be handled with appropriate safety measures to minimise radiation exposure (see section 4.4). Waterproof gloves and effective radiation shielding should be used when handling Pluvicto.

Patient identification

Patients should be identified for treatment by PSMA imaging.

Posology

The recommended Pluvicto dose is 7,400 MBq intravenously every 6 weeks (±1 week) for a total of 6 doses.

Treatment monitoring

Laboratory tests should be performed before and during treatment with Pluvicto.

• Haematology (haemoglobin, white blood cell count, absolute neutrophil count, platelet count)

• Kidney function (serum creatinine, calculated creatinine clearance [CLcr])

• Liver function (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, blood serum albumin, total blood bilirubin)

Dose modifications for adverse drug reactions (ADRs)

Recommended dose modifications of Pluvicto for ADRs are provided in Table 1. Management of severe or intolerable ADRs may require temporary dose interruption, dose reduction or permanent discontinuation of treatment with Pluvicto. If a treatment delay due to an adverse drug reaction persists for > 4 weeks, treatment with Pluvicto must be discontinued. The dose of Pluvicto may be reduced by 20% to 5 900 MBq once; the dose should not be re-escalated. If a patient has further adverse drug reactions that would require an additional dose reduction, treatment with Pluvicto must be discontinued.

Table 1 Recommended dose modifications of Pluvicto for ADRs

ADR

Severitya

Dose modification

Dry mouth

Grade ≥3

Reduce Pluvicto dose by 20% to 5 900 MBq.

Gastrointestinal toxicity

Grade ≥3 (not amenable to medical intervention)

Withhold Pluvicto until improvement to grade 2 or baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq.

Myelosuppresion

(anaemia, thrombocytopenia, leukopenia, neutropenia, pancytopenia)

Grade 2

Withhold Pluvicto until improvement to grade 1 or baseline.

Manage as deemed appropriate. The use of growth factors is permitted but should be discontinued once improved to grade 1 or baseline. Checking haematinic levels (iron, B12 and folate) and providing supplementation is advocated. Transfusions may be given as clinically indicated.

Grade ≥3

Withhold Pluvicto until improvement to Grade 1 or baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq.

Renal toxicity

Defined as:

• Confirmed serum creatinine increase (grade ≥2)

• Confirmed CLcr < 30 mL/min; calculate using Cockcroft‑Gault with actual body weight

Withhold Pluvicto until improvement.

Defined as:

• Confirmed ≥40% increase from baseline serum creatinine

and

• Confirmed >40% decrease from baseline CLcr; calculate using Cockcroft‑Gault with actual body weight

Withhold Pluvicto until improvement or return to baseline.

Reduce Pluvicto dose by 20% to 5 900 MBq.

Recurrent renal toxicity (grade ≥3)

Permanently discontinue Pluvicto.

Spinal cord compression

Any

Withhold Pluvicto until the compression has been adequately treated and any neurological sequela have stabilised and ECOG performance status has stabilised.

Fracture in weight‑bearing bones

Any

Withhold Pluvicto until the fracture has been adequately stabilised/treated and ECOG performance status has stabilised.

AST or ALT elevation

AST or ALT >20 times ULN in the absence of liver metastases

Permanently discontinue Pluvicto.

Abbreviations: CLcr, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ULN, upper limit of normal.

Grading according to most current Common Terminology Criteria for Adverse Events (CTCAE).

a The same thresholds are also applicable to baseline values at the time of treatment initiation with Pluvicto.

Special populations

Elderly

No dose adjustment is recommended in patients aged 65 years or older (see section 5.2).

Renal impairment

No dose adjustment is recommended for patients with mild (baseline CLcr 60 to 89 mL/min by Cockcroft‑Gault) to moderate (CLcr 30 to 59 mL/min) renal impairment. The pharmacokinetic profile and safety of Pluvicto have not been studied in patients with severe (CLcr 15 to 29 mL/min) renal impairment or end‑stage renal disease (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with hepatic impairment.

Paediatric population

There is no relevant use of Pluvicto in the paediatric population in the indication of treatment of PSMA‑expressing prostate cancer.

Method of administration

Pluvicto is for intravenous use. It is a ready to use radiopharmaceutical medicinal product for single use only.

Preparation instructions

• Aseptic technique and radiation shielding should be used when handling or administering Pluvicto, using tongs as needed to minimise radiation exposure.

• The product should be visually inspected under a shielded screen for particulate matter and discoloration prior to administration. The vial should be discarded if particulates or discoloration are present.

• The Pluvicto solution should not be injected directly into any other intravenous solution.

• The amount of radioactivity delivered to the patient should be confirmed with an appropriately calibrated dose calibrator prior to and after each Pluvicto administration.

Administration instructions

The recommended dose of Pluvicto may be administered intravenously as an injection using the syringe method, as an infusion using the gravity method, or as an infusion using the peristaltic pump method.

When using the gravity or peristaltic pump method, Pluvicto should be infused directly from its original container.

The syringe method or the peristaltic pump method should be used when administering a reduced dose of Pluvicto following a dose modification for an adverse reaction. When using the gravity method for a reduced dose, the Pluvicto dose should be adjusted before the administration to avoid the delivery of an incorrect volume of Pluvicto.

Prior to administration, the intravenous catheter used exclusively for Pluvicto administration should be flushed with ≥10 mL of 0.9% sterile sodium chloride solution to ensure patency and to minimise the risk of extravasation. Cases of extravasation should be managed as per institutional guidelines.

Intravenous methods of administration

Instructions for the syringe method

• Withdraw an appropriate volume of Pluvicto solution to deliver the desired radioactivity by using a disposable syringe fitted with a syringe shield and a disposable sterile needle that is 9 cm, 18 gauge (long needle). To aid the withdrawal of the solution, a filtered 2.5 cm, 20 gauge needle (short venting needle) can be used to reduce the resistance from the pressurised vial. Ensure that the short needle does not touch the Pluvicto solution in the vial.

• If using a syringe pump, fit the syringe into the shielded pump and include a 3-way stopcock valve between the syringe and an intravenous catheter primed with sterile sodium chloride 9 mg/mL (0.9%) solution for injection and used for Pluvicto administration to the patient.

• Administer Pluvicto to the patient by slow intravenous push within approximately 1 to 10 minutes (either with a syringe pump or manually without a syringe pump) via an intravenous catheter that is primed with 0.9% sterile sodium chloride solution and that is used exclusively for Pluvicto administration to the patient.

• When the desired Pluvicto radioactivity has been delivered, stop the syringe pump and then change the position of the 3-way stopcock valve to flush the syringe with 25 mL of sterile sodium chloride 9 mg/mL (0.9%) solution for injection. Restart the syringe pump.

• After the flush of the syringe has been completed, perform an intravenous flush of ≥10 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

Instructions for the gravity method

• Insert a 2.5 cm, 20 gauge needle (short needle) into the Pluvicto vial and connect via a catheter to 500 mL 0.9% sterile sodium chloride solution (used to transport the Pluvicto solution during the infusion). Ensure that the short needle does not touch the Pluvicto solution in the vial and do not connect the short needle directly to the patient. Do not allow the sodium chloride solution to flow into the Pluvicto vial prior to the initiation of the Pluvicto infusion and do not inject the Pluvicto solution directly into the sodium chloride solution.

• Insert a second needle that is 9 cm, 18 gauge (long needle) into the Pluvicto vial, ensuring that the long needle touches and is secured to the bottom of the Pluvicto vial during the entire infusion. Connect the long needle to the patient by an intravenous catheter that is primed with 0.9% sterile sodium chloride solution and that is used exclusively for the Pluvicto infusion into the patient.

• Use a clamp or an infusion pump to regulate the flow of the sodium chloride solution via the short needle into the Pluvicto vial (the sodium chloride solution entering the vial through the short needle will carry the Pluvicto solution from the vial to the patient via the intravenous catheter connected to the long needle within approximately 30 minutes).

• During the infusion, ensure that the level of solution in the Pluvicto vial remains constant.

• Disconnect the vial from the long needle line and clamp the saline line once the level of radioactivity is stable for at least five minutes.

• Follow the infusion with an intravenous flush of ≥10 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

Instructions for the peristaltic pump method

• Insert a filtered 2.5 cm, 20 gauge needle (short venting needle) into the Pluvicto vial. Ensure that the short needle does not touch the Pluvicto solution in the vial and do not connect the short needle directly to the patient or to the peristaltic pump.

• Insert a second needle that is 9 cm, 18 gauge (long needle) into the Pluvicto vial, ensuring that the long needle touches and is secured to the bottom of the Pluvicto vial during the entire infusion. Connect the long needle and a 0.9% sterile sodium chloride solution to a 3‑way stopcock valve via appropriate tubing.

• Connect the output of the 3‑way stopcock valve to tubing installed on the input side of the peristaltic pump according to manufacturer's instructions.

• Prime the line by opening the 3‑way stopcock valve and pumping the Pluvicto solution through the tubing until it reaches the exit of the valve.

• Prime the intravenous catheter which will be connected to the patient by opening the 3‑way stopcock valve to the 0.9% sterile sodium chloride solution and pumping the 0.9% sterile sodium chloride solution until it exits the end of the catheter tubing.

• Connect the primed intravenous catheter to the patient and set the 3‑way stopcock valve such that the Pluvicto solution is in line with the peristaltic pump.

• Infuse an appropriate volume of Pluvicto solution at approximately 25 mL/h to deliver the desired radioactivity.

• When the desired Pluvicto radioactivity has been delivered, stop the peristaltic pump and then change the position of the 3‑way stopcock valve so that the peristaltic pump is in line with the 0.9% sterile sodium chloride solution. Restart the peristaltic pump and infuse an intravenous flush of ≥10 mL of 0.9% sterile sodium chloride solution through the intravenous catheter to the patient.

For patient preparation, see section 4.4.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Individual benefit/risk justification

For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required therapeutic effect.

Risk from radiation exposure

Pluvicto contributes to a patient's overall long‑term cumulative radiation exposure. Long‑term cumulative radiation exposure is associated with an increased risk for cancer.

Radiation exposure to patients, medical personnel, and others should be minimised during and after treatment with Pluvicto consistent with institutional good radiation safety practices, patient management procedures, and instructions to the patient for follow‑up radiation protection at home.

Patient preparation

Patients should be encouraged to increase oral fluids and urged to void as often as possible to reduce bladder radiation, especially after high activities, e.g. for radionuclide therapy.

After the procedure

Before the patient is released, the nuclear medicine physician or healthcare provider should explain the necessary radioprotection precautions that the patient should follow to minimise radiation exposure to others.

Following administration of Pluvicto, patients should be advised to:

• limit close contact (less than 1 meter) with others for 2 days or with children and pregnant women for 7 days.

• refrain from sexual activity for 7 days.

• sleep in a separate room from others for 3 days, from children for 7 days, or from pregnant women for 15 days.

Myelosuppression

In the PSMAfore study, myelosuppression occurred more frequently in patients who received Pluvicto compared to patients who switched to another ARPI therapy (see section 4.8)

In the VISION study, myelosuppression occurred more frequently in patients who received Pluvicto plus best standard of care (BSoC) compared to patients who received BSoC alone (see section 4.8).

Haematology laboratory tests, including haemoglobin, white blood cell count, absolute neutrophil count and platelet count, should be performed before and during treatment with Pluvicto. Pluvicto should be withheld, dose reduced, or permanently discontinued and patients should be clinically managed as deemed appropriate based on the severity of myelosuppression (see section 4.2).

Renal toxicity

In the PSMAfore study, renal toxicity was comparable in patients who received Pluvicto compared to patients who switched to another ARPI therapy (see section 4.8)

In the VISION study, renal toxicity occurred more frequently in patients who received Pluvicto plus BSoC compared to patients who received BSoC alone (see section 4.8).

Patients should be advised to remain well hydrated and to urinate frequently before and after administration of Pluvicto. Kidney function laboratory tests, including serum creatinine and calculated CLcr, should be performed before and during treatment with Pluvicto. Pluvicto should be withheld, dose reduced, or permanently discontinued based on the severity of renal toxicity (see section 4.2).

Renal/Hepatic impairment

Careful consideration of the benefit risk ratio in these patients is required since an increased radiation exposure is possible.

Exposure (AUC) of lutetium (177Lu) vipivotide tetraxetan is expected to increase with the degree of renal impairement (see section 5.2). Patients with mild or moderate renal impairment may be at greater risk of toxicity. Renal function and adverse drug reactions should be frequently monitored in patients with mild to moderate renal impairment (see section 4.2). The pharmacokinetic profile and safety of lutetium (177Lu) vipivotide tetraxetan have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or end-stage renal disease.

Specific warnings

Sodium content

This medicinal product contains up to 3.9 mmol (88.75 mg) sodium per dose, equivalent to 4.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Precautions with respect to environmental hazard see section 6.6.

4.5. Interaction with other medicinal products and other forms of interaction

No clinical drug interaction studies were required.

4.6. Fertility, pregnancy and lactation

Contraception in males

Based on its mechanism of action, male patients should be advised not to father a child and to use condoms for intercourse during treatment with Pluvicto and for 14 weeks after the last dose.

Pregnancy

The safety and efficacy of Pluvicto have not been established in females as Pluvicto is not indicated for use in females. No animal studies using lutetium (177Lu) vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo‑foetal development; however, all radioactive emissions, including those from Pluvicto, can cause foetal harm. Based on its mechanism of action, Pluvicto can cause foetal harm when administered to a pregnant woman (see section 5.1).

Breast‑feeding

The safety and efficacy of Pluvicto have not been established in females as Pluvicto is not indicated for use in females. There are no data on the presence of lutetium (177Lu) vipivotide tetraxetan in human milk or its effects on the breast‑fed newborn/infant or on milk production.

Fertility

No studies were conducted to determine the effects of lutetium (177Lu) vipivotide tetraxetan on fertility. The recommended cumulative dose of 44,400 MBq of Pluvicto results in a radiation absorbed dose to the testes within the range where Pluvicto may cause infertility.

4.7. Effects on ability to drive and use machines

Pluvicto has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Exposure to ionising radiation is linked with cancer induction and a potential for development of hereditary defects. The radiation dose resulting from therapeutic exposure may result in higher incidence of cancer and mutations. In all cases it is necessary to ensure that the risks of the radiation are less than from the disease itself.

PSMAfore Study: Summary of the safety profile

The safety of Pluvicto was evaluated in the Phase III PSMAfore study in patients with progressive, PSMA-positive mCRPC previously treated with ARPI therapy. Of the 468 patients randomised, 459 patients received at least one dose of randomised treatment. Patients received either Pluvicto 7,400 MBq administered every 6 weeks (N = 227) or a change in ARPI (N = 232).

Among patients who received Pluvicto, the median number of doses of Pluvicto received was 6 (range: 1 to 6), with 63.4% of patients who received all 6 doses of Pluvicto. The median cumulative dose of Pluvicto was 42,400 MBq (range: 7,000 to 45,400). The median duration of exposure to randomised treatment was 8.4 months (range: 0.4 to 11.6) for patients who received Pluvicto and 6.5 months (range: 0.03 to 29.2) for patients who received a change in ARPI. The data analyses presented below do not include patients who crossed over to receive Pluvicto after receiving treatment in the change in ARPI arm.

Table 2 summarises the incidence of adverse drug reactions. The most common adverse drug reactions (≥20%) in patients who received Pluvicto include: dry mouth (60.8%), fatigue (52.9%), nausea (31.7%), anaemia (27.3%), constipation (22.0%) and decreased appetite (21.6%). The most common Grade 3 to 4 adverse drug reactions (≥5%) in patients who received Pluvicto include: anaemia (6.2%).

Tabulated list of ADRs

ADRs (Table 2) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 2 Adverse drug reactions in patients who received Pluvicto compared to a change in ARPI in PSMAforea

ADRs

Frequency category

All grades

n (%)

Grades 3 to 4b

n (%)

Infections and infestations

Urinary tract infectionc

Common

13 (5.7)

3 (1.3)

Oral fungal infectiond

Common

7 (3.1)

0

Blood and lymphatic system disorders

Anaemia

Very common

62 (27.3)

14 (6.2)

Leukopeniae

Very common

25 (11.0)

5 (2.2)

Thrombocytopenia

Very common

23 (10.1)

7 (3.1)

Lymphopenia

Common

15 (6.6)

10 (4.4)

Pancytopenia

Uncommon

1 (0.4)

0

Metabolism and nutrition disorders

Decreased appetite

Very common

49 (21.6)

0

Nervous system disorders

Dysgeusiaf

Common

20 (8.8)

0

Headache

Common

19 (8.4)

0

Dizziness

Common

10 (4.4)

0

Eye disorders

Dry eyeg

Common

14 (6.2)

0

Ear and labyrinth disorders

Vertigo

Common

4 (1.8)

0

Gastrointestinal disorders

Dry mouthh

Very common

138 (60.8)

2 (0.9)

Nausea

Very common

72 (31.7)

0

Constipation

Very common

50 (22.0)

1 (0.4)

Diarrhoea

Very common

38 (16.7)

0

Vomiting

Very common

26 (11.5)

0

Abdominal paini

Common

21 (9.3)

2 (0.9)

Oesophageal disorderj

Common

9 (4.0)

1 (0.4)

Stomatitis

Common

3 (1.3)

1 (0.4)

Skin and subcutaneous tissue disorders

Dry Skin

Common

9 (4.0)

0

Renal and urinary disorders

Acute kidney injuryl

Common

15 (6.6)

3 (1.3)

General disorders and administration site conditions

Fatiguem

Very common

120 (52.9)

3 (1.3)

Oedema peripheral

Common

19 (8.4)

0

Pyrexia

Common

6 (2.6)

1 (0.4)

Investigations

Weight decreased

Common

15 (6.6)

1 (0.4)

Abbreviation: ARPI, androgen receptor pathway inhibitor.

*Patients in the Pluvicto arm do not include patients who crossed over to receive Pluvicto after receiving treatment in the change in ARPI arm.

aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

bOnly includes Grades 3 to 4 adverse drug reactions, no grade 5 adverse drug reactions recorded during treatment phase.

cUrinary tract infection includes urinary tract infection, cystitis, and urinary tract infection enterococcal.

dOral fungal infection includes candida infection, oral candidiasis, oral fungal infection, and oropharyngeal candidiasis.

eLeukopenia includes neutropenia and leukopenia.

fDysgeusia includes dysgeusia and taste disorder.

gDry eye includes dry eye and xerophthalmia.

hDry mouth includes dry mouth, mucosal dryness, salivary hyposecretion, dry throat, and lip dry.

iAbdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, and epigastric discomfort.

jOesophageal disorder includes gastrooesophageal reflux disease, dysphagia, oesophagitis, and burn oesophageal.

kDry skin includes xerosis and dry skin.

lAcute kidney injury includes blood creatinine increased, acute kidney injury, renal failure, and blood urea increased.

mFatigue includes asthenia and fatigue.

Description of selected ADRs

Myelosuppression

In the PSMAfore study, myelosuppression occurred more frequently in patients who received Pluvicto compared to patients who received a change in ARPI (all Grades/Grade ≥3): anaemia (26.9%/6.2%) versus (19.0%/6.9%); thrombocytopenia (7.5%/2.2%) versus (3.0%/0.9%); neutropenia (5.7%/1.3%) versus (0.9%/0.4%); leukopenia (2.2%/0.9%) versus (0%/0%); lymphopenia (1.8%/0.4%) versus (0%/0%); and pancytopenia (0.4%/0%) versus (0.4%/0%). One fatal case of bone marrow failure occurred during the long term follow-up period in a patient treated with Pluvicto.

Myelosuppression adverse drug reactions that led to permanent discontinuation in ≥0.5% of patients who received Pluvicto included: thrombocytopenia (1.3%). Myelosuppression adverse drug reactions that led to dose interruptions /dose reductions in ≥0.5% of patients who received Pluvicto included: anaemia (1.8%/0.4%) and neutropenia (0.9%/0.4%).

Renal toxicity

In the PSMAfore study, renal toxicity was comparable in patients who received Pluvicto compared to patients who received a change in ARPI (all Grades/Grade 3 to 4): blood creatinine increased (4.4%/0%) versus (3.0%/0%); acute kidney injury (2.2%/1.3%) versus (3.9%/2.2%); renal failure (0.9%/0.4%) versus (1.3%/0.9%); and blood urea increased (0.4%/0%) versus (0%/0%).

Renal adverse drug reactions that led to permanent discontinuation in ≥0.4% of patients who received Pluvicto included: acute kidney injury (0.4%). Renal adverse drug reactions that led to dose interruptions /dose reductions in ≥0.4% of patients who received Pluvicto included: blood creatinine increased (0.4%/0%) and renal failure (0.4%/0%).

VISION Study: Summary of the safety profile

The safety of Pluvicto was evaluated in the phase III VISION study in patients with progressive, PSMA‑positive mCRPC. Of the 831 patients randomised, 734 patients received at least one dose of randomised treatment. Patients received at least one dose of either Pluvicto 7,400 MBq administered every 6 to 10 weeks plus BSoC (n=529) or BSoC alone (n=205).

Among patients who received Pluvicto plus BSoC, the median number of doses of Pluvicto received was 5 (range: 1 to 6), with 67.7% of patients who received at least 4 doses of Pluvicto and 46.5% of patients who received a total of 6 doses of Pluvicto. The median cumulative dose of Pluvicto was 37,500 MBq (range: 7,000 to 48,300). The median duration of exposure to randomised treatment was 7.8 months (range: 0.3 to 24.9) for patients who received Pluvicto plus BSoC and 2.1 months (range: 0.0 to 26.0) for patients who received BSoC alone.

Table 3 summarises the incidence of ADRs. The most common ADRs (≥20%) occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone include: fatigue (48.0%), dry mouth (39.3%), nausea (35.7%), anaemia (31.9%), decreased appetite (21.4%) and constipation (20.2%). The most common grade 3 to 4 ADRs (≥5%) occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone include: anaemia (12.9%), thrombocytopenia (7.9%), lymphopenia (7.8%) and fatigue (6.6%).

At the time of VISION final analysis, after a median follow-up duration of 14.2 months (range: 0.6 to 60.9 months), the overall safety profile remained consistent with that previously reported.

Tabulated list of ADRs

ADRs (Table 3) are listed by MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each ADR is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 3 ADRs occurring at a higher incidence in patients who received Pluvicto plus BSoC compared to BSoC alone in VISIONa

ADRs

Frequency category

All grades

n (%)

grades 3 to 4b

n (%)

Infections and infestations

Oral fungal infectionc

Common

13 (2.5)

0 (0.0)

Blood and lymphatic system disorders

Anaemia

Very common

169 (31.9)

68 (12.9)

Thrombocytopenia

Very common

91 (17.2)

42 (7.9)

Leukopeniad

Very common

83 (15.7)

22 (4.2)

Lymphopenia

Very common

75 (14.2)

41 (7.8)

Pancytopeniae

Common

9 (1.7)

7 (1.3)b

Bone marrow failure

Uncommon

1 (0.2)

1 (0.2)b

Nervous system disorders

Dizziness

Common

44 (8.3)

5 (0.9)

Headache

Common

37 (7.0)

4 (0.8)

Dysgeusiaf

Common

37 (7.0)

0 (0.0)

Eye disorders

Dry eye

Common

16 (3.0)

0 (0.0)

Ear and labyrinth disorders

Vertigo

Common

11 (2.1)

0 (0.0)

Gastrointestinal disorders

Dry mouthg

Very common

208 (39.3)

0 (0.0)

Nausea

Very common

189 (35.7)

7 (1.3)

Constipation

Very common

107 (20.2)

6 (1.1)

Vomitingh

Very common

101 (19.1)

5 (0.9)

Diarrhoea

Very common

101 (19.1)

4 (0.8)

Abdominal paini

Very common

61 (11.5)

7 (1.3)

Oesophageal disorderj

Common

18 (3.4)

1 (0.2)

Stomatitis

Common

9 (1.7)

1 (0.2)

Skin and subcutaneous tissue disorders

Dry skink

Common

8 (1.5)

0 (0.0)

Renal and urinary disorders

Urinary tract infectionl

Very common

63 (11.9)

20 (3.8)

Acute kidney injurym

Common

48 (9.1)

18 (3.4)

General disorders and administration site conditions

Fatiguen

Very common

254 (48.0)

35 (6.6)

Decreased appetite

Very common

113 (21.4)

10 (1.9)

Weight decreased

Very common

58 (11.0)

2 (0.4)

Oedema peripheralo

Common

53 (10.0)

2 (0.4)

Pyrexia

Common

37 (7.0)

2 (0.4)

Abbreviation: BSoC, best standard of care.

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.

b Only includes grades 3 to 4 ADRs, with the exception of pancytopenia and bone marrow failure. Grade 5 (fatal) pancytopenia was reported in 2 patients who received Pluvicto plus BSoC. Grade 5 (fatal) bone marrow failure was reported in 1 patient who received Pluvicto plus BSoC.

c Oral fungal infection includes oral candidiasis, candida infection, oral fungal infection, oropharyngitis fungal and tongue fungal infection.

d Leukopenia includes leukopenia and neutropenia.

e Pancytopenia includes pancytopenia and bicytopenia.

f Dysgeusia includes dysgeusia and taste disorder.

g Dry mouth includes dry mouth, lip dry, salivary hyposecretion and dry throat.

h Vomiting includes vomiting and retching.

i Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, abdominal tenderness and gastrointestinal pain.

j Oesophageal disorder includes gastrooesophageal reflux disease, dysphagia and oesophagitis.

k Dry skin includes dry skin and xeroderma.

l Urinary tract infection includes urinary tract infection, cystitis and cystitis bacterial.

m Acute kidney injury includes blood creatinine increased, acute kidney injury, renal failure and blood urea increased.

n Fatigue includes fatigue and asthenia.

o Oedema peripheral includes oedema peripheral, fluid retention and hypervolaemia.

Description of selected ADRs

Myelosuppression

In the VISION study, myelosuppression occurred more frequently in patients who received Pluvicto plus BSoC compared to patients who received BSoC alone (all grades/grade ≥3): anaemia (31.9%/12.9%) versus (13.2%/4.9%); thrombocytopenia (17.2%/7.9%) versus (4.4%/1.0%); leukopenia (12.5%/2.5%) versus (2.0%/0.5%); lymphopenia (14.2%/7.8%) versus (3.9%/0.5%); neutropenia (8.5%/3.4%) versus (1.5%/0.5%); pancytopenia (1.5%/1.1%) versus (0%/0%) including two fatal events of pancytopenia in patients who received Pluvicto plus BSoC; and bicytopenia (0.2%/0.2%) versus (0%/0%);and bone marrow failure (0.2%/0.2%) versus (0%/0%) including one fatal event of bone marrow failure in a patient who received Pluvicto plus BSoC.

Myelosuppression ADRs that led to permanent discontinuation in ≥0.5% of patients who received Pluvicto plus BSoC included: anaemia (2.8%), thrombocytopenia (2.8%), leukopenia (1.3%), neutropenia (0.8%) and pancytopenia (0.6%). Myelosuppression ADRs that led to dose interruptions/dose reductions in ≥0.5% of patients who received Pluvicto plus BSoC included: anaemia (5.1%/1.3%), thrombocytopenia (3.6%/1.9%), leukopenia (1.5%/0.6%) and neutropenia (0.8%/0.6%).

Renal toxicity

In the VISION study, renal toxicity occurred more frequently in patients who received Pluvicto plus BSoC compared to patients who received BSoC alone (all grades/grades 3 to 4): blood creatinine increased (5.7%/0.2%) versus (2.4%/0.5%); acute kidney injury (3.8%/3.2%) versus (3.9%/2.4%); renal failure (0.2%/0%) versus (0%/0%); and blood urea increased (0.2%/0%) versus (0%/0%).

Renal ADRs that led to permanent discontinuation in ≥0.2% of patients who received Pluvicto plus BSoC included: blood creatinine increased (0.2%). Renal ADRs that led to dose interruptions/dose reductions in ≥0.2% of patients who received Pluvicto plus BSoC included: blood creatinine increased (0.2%/0.4%) and acute kidney injury (0.2%/0%).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of administration of a radiation overdose with Pluvicto, the radiation absorbed dose to the patient should be reduced where possible by increasing the elimination of the radionuclide from the body by frequent micturition or by forced diuresis and frequent bladder voiding. It might be helpful to estimate the effective radiation dose that was applied.